Sc Insulin Research Articles

Continuous SC insulin infusion “worthwhile investment” in diabetes

Continuous SC insulin infusion “worthwhile investment” in diabetes

Continuous SC insulin infusion "worthwhile investment" in diabetes

Continuous SC insulin infusion "worthwhile investment" in diabetes

The rationale and management of hyperglycemia for in-patients with cardiovascular disease: time for change.

There is increasing evidence that aggressive glycemic control for patients admitted into the hospital improves clinical outcomes, especially for patients with cardiovascular disease. There appear to be a variety of mechanisms for this. Although hyperglycemia has been shown to result in poor wound healing and more infectious complications, especially after cardiac surgical procedures, what has become clear is that the treatment of hyperglycemia with i.v. glucose, insulin, and potassium (GIK) results in better clinical outcomes even in patients without diabetes. The mechanisms for this are not year clear, but could be related to the insulin administration, perhaps due to suppression of various cytokines or free fatty acids. The practical use of insulin in these patients requires basic understanding of the use of both i.v. and s.c. insulin. Although there are several appropriate options for both of these routes of administration, it is critical that all caregivers involved in this population's care are knowledgeable about insulin strategies.

Abdominal obesity, muscle composition, and insulin resistance in premenopausal women.

The independent relationships between visceral and abdominal sc adipose tissue (AT) depots, muscle composition, and insulin sensitivity were examined in 40 abdominally obese, premenopausal women. Measurements included glucose disposal by euglycemic clamp, muscle composition by computed tomography, abdominal and nonabdominal (e.g. leg) AT by magnetic resonance imaging and cardiovascular fitness. Glucose disposal rates were negatively related to visceral AT mass (r = -0.42, P < 0.01). These observations remained significant (P < 0.01) after control for nonabdominal and abdominal sc AT, muscle attenuation, and peak oxygen uptake. Total, abdominal, or leg sc AT or muscle attenuation was not significantly (P > 0.10) related to glucose disposal. Subdivision of abdominal sc AT into anterior and posterior depots did not alter the observed relationships. Further analysis matched two groups of women for abdominal sc AT but with low and high visceral AT. Women with high visceral AT had lower glucose disposal rates compared with those with low visceral AT (P < 0.05). A similar analysis performed on two groups of women matched for visceral AT but high and low abdominal sc AT revealed no statistically different values for insulin sensitivity (P > 0.10). In conclusion, visceral AT alone is a strong correlate of insulin resistance independent of nonabdominal, abdominal sc AT, muscle composition, and cardiovascular fitness. Subdivision of abdominal sc AT did not provide additional insight into the relationship between abdominal obesity and metabolic risk.

Efficacy and safety of insulin aspart compared to buffered human insulin by continuous SC insulin infusion

Efficacy and safety of insulin aspart compared to buffered human insulin by continuous SC insulin infusion

Continuous SC insulin lispro provides superior glycaemic control

Continuous SC insulin lispro provides superior glycaemic control

Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221 cases (1993-1998).

To evaluate glycemic response to insulin treatment in dogs with diabetes mellitus. Retrospective study. 221 dogs with diabetes mellitus. Type and dosage of insulin used, minimum and maximum blood glucose concentrations, time of blood glucose concentration nadir, and optimal duration of action of insulin were determined on the basis of data obtained prior to initial examination at the teaching hospital (127 dogs), at the time of initial examination (212 dogs), at the time a second follow-up blood glucose curve was performed (59 dogs), and at the time of clinical control of diabetes mellitus (83 dogs). Prior to examination, 69 of 127 dogs (54%) received 1 s.c. insulin injection daily. Thirty-one dogs (24%) received a high dose of insulin (i.e., > 1.5 U/kg [0.7 U/lb] of body weight); 27 of these dogs (87%) received 1 injection/d. Eleven of 16 dogs (69%) that were hypoglycemic (blood glucose concentration < 80 mg/dl) also received 1 injection/d. However, optimal duration of action of insulin was > 12 hours in only 5 of 83 dogs (6%) evaluated at the time diabetes mellitus was clinically controlled. At that time, only 1 dog (1%) received a high dose of insulin, and the dog received 2 injections/d. Moreover, 8 of 10 dogs (80%) with hypoglycemia received 1 injection/d. Most dogs with diabetes mellitus are clinically regulated with 2 daily insulin injections. Administration of a high dose of insulin or development of hypoglycemia may be more common in diabetic dogs that receive insulin once daily, compared with dogs that receive insulin twice daily.

Continuous SC insulin infusion improves metabolic control

Continuous SC insulin infusion improves metabolic control

Changes in the growth hormone-IGF-I axis in non-obese diabetic mice.

We investigated the changes in GH-IGF-I axis in non-obese diabetic (NOD)-mice, a model of insulin dependent diabetes mellitus. Diabetic female NOD mice and their age- and sex-matched controls were sacrificed at 4, 14, 21 and 30 days (30d DM) after the onset of glycosuria. Serum GH levels increased and serum IGF-I levels decreased in the 30d DM group (182 ± 32% and 45 ± 24% of age-matched controls respectively, p < 0.05). Another group (30d DM + I) was given SC insulin, and its serum IGF-I levels remained decreased. Liver GH receptor (GHR) and GH binding protein (GHBP) mRNA levels, as well as liver membrane GH binding assays were deeply decreased in the 30d DM group in comparison to controls. GHR message and binding capacity remained decreased in the 30d DM + I group. Renal GHR mRNA was decreased at 21d DM but not at 14d DM, whereas GHBP mRNA remained unchanged throughout the experiment. In conclusion, increased serum GH levels are documented in NOD diabetic mice, similarly to the changes described in humans. The decrease in GHR levels and decreased serum IGF-I in spite of increased circulating GH suggest a state of GH resistance.

Reduced glucose availability attenuates circadian responses to light in mice.

To test whether circadian responses to light are modulated by decreased glucose availability, we analyzed photic phase resetting of the circadian rhythm of locomotor activity in mice exposed to four metabolic challenges: 1) blockade of glucose utilization induced by 2-deoxy-D-glucose (2-DG), 2) fasting (food was removed for 30 h), 3) insulin administration, and 4) insulin treatment after fasting. In mice housed in constant darkness, light pulses applied during early subjective night induced phase delays of the rhythm of locomotor activity, whereas light pulses applied during late subjective night caused phase advances. There was an overall reduction of light-induced phase shifts, with a more pronounced effect for delays, in mice pretreated with 500 mg/kg ip 2-DG compared with mice injected with saline. Administration of glucose with 2-DG prevented the reduction of light-induced phase delays. Furthermore, phase delays were reduced in fed mice pretreated with 5 IU/kg sc insulin and in fasted mice injected with saline or insulin compared with control fed mice. These results show that circadian responses to light are reduced when brain glucose availability is decreased, suggesting a metabolic modulation of light-induced phase shifts.

Diabetics take a deep breath for future therapy

A revolution in the treatment of patients with diabetes is fast approaching. Two phase II clinical trials with inhaled insulin have shown that an aerosol formulation gives glycaemic control equivalent to that of SC insulin. Decreases in fasting and postprandial blood glucose levels were similar in patients treated with either inhaled or injected insulin during 3 months of treatment. Also, the incidence of hypoglycaemia did not differ between treatments. Results from the 2 studies show that these effects were similar in patients with type 1 and type 2 diabetes. Pharmacokinetic and pharmacodynamic data indicate that the aerosol formulation has a more rapid onset of action, compared with injected insulin, leading to a faster lowering of blood glucose levels, investigators reported at the American Diabetes Association meeting [Chicago, US; June 1998].

Benefits of nocturnal continuous SC insulin infusion

Benefits of nocturnal continuous SC insulin infusion

Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY)

Hypoglycemia causes hyperphagia and weight gain, through unknown peripheral and central signals. We investigated the effect of hypoglycemia on NPY and leptin expression and the ability of leptin to inhibit hypoglycemia-induced hyperphagia. Acute hypoglycemia (60 U/kg SC insulin; n = 8) increased food intake ( p < 0.01) compared with controls ( n = 8). Insulin- and leptin-treated rats (300 μg/kg IP leptin; n = 8) had reduced hyperphagia ( p < 0.05 vs. controls; p < 0.05 vs. insulin alone) and a 15% fall in NPY mRNA levels compared with controls ( p < 0.01). Chronic hypoglycemia, (20–60 U/kg/day insulin; n = 8) increased food intake compared with vehicle-treated controls ( p < 0.01). Leptin and insulin administration (300 μg/kg/day IP leptin; n = 8) reduced hyperphagia ( p < 0.01 vs. controls, p < 0.05 vs. insulin alone), and NPY mRNA fell by 18% vs. controls ( p < 0.01). We conclude that hypoglycemia-induced hyperphagia is not mediated by either a fall in leptin or an increase in hypothalamic NPY mRNA. Leptin can inhibit feeding in hyperphagic hypoglycemic rats, and this may partly be attributable to its inhibition of the NPY neurons.

The degree/rapidity of the metabolic deterioration following interruption of a continuous subcutaneous insulin infusion is influenced by the prevailing blood glucose Level.

This study aims at investigating the influence of the prevailing blood glucose level on the metabolic deterioration that follows a nocturnal interruption of a continuous sc insulin infusion (CSII). Fifteen CSII-treated, C-peptide negative, diabetic patients have been studied CSII was interrupted from 2300 h to 0500 h. Blood was collected hourly from 2200 h to 0600 h. According to blood glucose (BG) levels at 2300 h, patients were classified as hypoglycemic (BG between 1.5 and 2.5 mmol/L, n = 5), normoglycemic (BG between 4.0 and 8.0 mmol/L, n = 5), or hyperglycemic (BG between 9.0 and 15.0 mmol/L, n = 5). At 2300 h, BG (mean +/- SEM) was 1.9 +/- 0.1, 6.2 +/- 0.7 and 11.2 +/- 1.0 mmol/L, respectively. After 6 h of CSII interruption, BG increased to 13.5 +/- 1.3, 14.1 +/- 1.2, and 19.4 +/- 1.2 mmol/L, respectively. At 2300 h, plasma 3-OH-butyrate levels were similar in the three groups (around 150 micromol/L). At 0500 h, significantly higher values were obtained for hyperglycemic (1460 +/- 127 micromol/L) than for normoglycemic (868 +/- 150 micromol/L) or hypoglycemic (837 +/- 80 micromol/L) patients. Enhanced lipolysis in initially hyperglycemic patients may contribute to accelerated ketogenesis and metabolic degradation. In conclusion, the metabolic deterioration that follows CSII interruption is influenced by the initial metabolic situation. Hypoglycemic patients deteriorate more rapidly, and hyperglycemic patients suffer a more important degradation. The latter are prone to rapid ketoacidosis if accidental CSII interruption occurs.

Nocturnal blood pressure elevation is related to adrenomedullary hyperactivity, but not to hyperinsulinemia, in nonobese normoalbuminuric type 1 diabetes.

We tested the hypothesis that insulin is an independent risk factor for elevated blood pressure. As our model we selected type 1 diabetes with peripheral circulatory hyperinsulinemia induced by sc insulin treatment. In 15 nonobese normoalbuminuric patients with type 1 diabetes (23.7 +/- 0.8 yr old) and in 15 healthy controls matched for age, sex, and body weight, ambulatory blood pressure was recorded over 24 h. The areas under the curve of free insulin (605 +/- 135 vs. 275 +/- 35 pmol/L.h; P = 0.03) and basal plasma epinephrine concentrations were higher (170 +/- 10 vs. 130 +/- 10 pmol/L; P = 0.02), and the basal aldosterone level was lower (220 +/- 40 vs. 410 +/- 50 pmol/L; P = 0.009) in the patients. The nocturnal decline in systolic blood pressure was less pronounced (13 +/- 1 vs. 19 +/- 2 mm Hg; P = 0.007) in the patients. Multivariate adjustment (r2 = 0.75; P = 0.0002) showed an effect of basal plasma epinephrine and norepinephrine levels and body mass index on the mean nocturnal systolic blood pressure, but showed no effect of age, sex, hemoglobin A1c, aldosterone, or, in particular, insulin. We found a blunted nocturnal fall in blood pressure in nonobese, normoalbuminuric type 1 diabetic patients. These patients showed increased adrenomedullary activity, and this predominantly contributed to the blood pressure alterations. We also found hyperinsulinemia in these patients, but, after controlling for covariates, blood pressure was independent of the insulin level.

IP vs SC insulin in intensive diabetes management

IP vs SC insulin in intensive diabetes management

IP vs SC insulin in intensive diabetes management

IP vs SC insulin in intensive diabetes management

Could intranasal insulin be useful in the treatment of non-insulin-dependent diabetes mellitus?

To evaluate whether intranasal insulin might be useful as a meal-adjunct in the treatment of NIDDM we compared plasma glucose and insulin responses to a mixed breakfast (9 kcal/kg, 50% carbohydrate) following either intranasal insulin (INI) or placebo in eleven patients with NIDDM. Five patients treated with subcutaneous insulin and in good to moderate glycemic control and six patients who were ‘failing’ on oral agents and in poor glycemic control were studied. In the patients usually on sc insulin, INI inhibited postprandial hyperglycemia. Lower doses (1 U/kg vs 1.5 U/kg b.w.) were needed to accomplish this in 2 patients with low fasting glucose (≤7.8 mmol/l) than in three patients with higher fasting glucose (10.5 ± 0.5 mmol/l). In the patients on oral agents who had marked fasting hyperglycemia (14.8 ± 0.8 mmol/l) an only transient reduction (for 90 to 120 min) of postprandial hyperglycemia was achieved when INI (1 U/kg) was given in addition to po glyburide (10 mg) prior to the meal. Following placebo in the group previously treated with sc insulin, plasma free insulin levels increased maximally by 23 mU/l, 75 min after the meal. The group on oral agents had a comparable but later peak increment (at 180 min) indicative of an even greater impairment of endogenous insulin secretion in response to hyperglycemia. Following INI, the peak increment in plasma insulin occurred earlier (30 min after the meal) and was greater in all patients (55 ± 18, 139 ± 68, 86 ± 24 mU/l respectively for the prior sc insulin therapy group at doses of 1.0 and 1.5 U/kg and for the oral agent group at 1.0 U/kg). In summary, intranasal insulin can reduce postprandial hyperglycemia in patients with NIDDM by increasing early postprandial insulin levels. It is more effective in those with less severe fasting hyperglycemia. Since elevated insulin levels and glucose lowering effect are transient, nasal insulin would need to be added to a regimen achieving fasting glucose control through diet, oral agents or long-acting subcutaneous insulin.

The Contribution of Intermediate‐acting Insulin Preparations to Daytime Insulin Treatment

Hyperglycaemia in the afternoon is often not prevented by increasing the intermediate insulin dose in C-peptide deficient Type 1 diabetic patients, particularly children, treated with two injections of mixtures of short- and intermediate-acting insulins. To provide a better understanding of this, 19 Type 1 diabetic patients were studied using the euglycaemic clamp technique, after SC injection of either soluble, isophane (NPH) or lente insulin, or mixtures of these preparations. SC injection of 0.6 U kg-1 insulin, as either intermediate-acting (isophane (NPH) or lente) insulin alone or as a mixture of 50% soluble + 50% intermediate-acting insulins, indicates that, for the same total dose of SC insulin, a shift from soluble to intermediate-acting insulin results in a major loss of activity during the first 6 h after injection, with no compensatory increase over the next 6 h. The morning hypoglycaemic activity depends on different mechanisms with isophane (NPH) or lente insulin; the effects of soluble and isophane (NHP) insulin are superimposed, while with lente insulin, the peak of soluble insulin is blunted. For the afternoon, even large doses of isophane (NPH) or lente insulin do not meet the peak of insulin requirements following lunch.

Porcine and human insulin absorption from subcutaneous tissues in normal and insulin-dependent diabetic subjects: a deconvolution-based approach.

The mechanisms of sc insulin absorption are not understood, and models for interpreting in vivo data cannot be developed without gross simplification. To overcome this difficulty we developed a new approach which makes use of deconvolution analysis and does not require any model of the sc tissue. In five normal subjects and seven insulin-dependent diabetic (IDDM) patients endogenous insulin secretion was suppressed by means of a hypoglycemic glucose clamp procedure (approximately 2.8 mmol/L) sustained by a continuous insulin infusion (approximately 4 pmol/min.kg). A bolus injection of insulin (5.4 nmol) was administered iv, and plasma insulin concentrations were measured frequently for 2 h to assess iv insulin kinetics. Insulin then was injected sc in the abdominal region, and plasma insulin concentrations were measured for 8 h. Each subject was studied twice, with porcine and semisynthetic human insulin (Actrapid, Novo). The rate of insulin absorption was reconstructed by deconvolution from the plasma concentrations and iv insulin kinetic data. Linearity of the iv insulin kinetics, essential for deconvolution analysis, was confirmed by a dose-response study in the range of the measured concentrations (150-1800 pmol/L). In most instances, a two-compartment model was adequate to describe the iv response. The mean plasma insulin clearance rates were 15.5 +/- 1.9 (+/- SD) mL/min.kg (porcine) and 17.2 +/- 6.0 (human) in normal subjects and 20.7 +/- 8.8 (porcine) and 20.9 +/- 9.1 (human) in the IDDM patients. The rate of appearance of human insulin from sc tissue was faster than that of porcine insulin in both normal and IDDM subjects, but no significant differences were found in bioavailability, which was 55 +/- 12% (+/- SD; porcine) and 61 +/- 34% (human) in the normal subjects, and 84 +/- 28% (porcine) and 86 +/- 23% (human) in the IDDM patients. The rate of absorption and bioavailability were higher in the IDDM patients than in the normal subjects, a difference possibly related to increased sc blood flow in the IDDM patients. No differences were found with regard to glucose requirement values, normalized to plasma insulin concentrations, in agreement with the finding that the bioavailability of the two insulin species was similar.